Journal
MOLECULAR ONCOLOGY
Volume 7, Issue 6, Pages 1116-1128Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.molonc.2013.08.007
Keywords
CAFs; c-Ski; P53; SDF-1; Tumor microenvironment
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Funding
- National Natural Science Foundation of China [NSFC 81072147, NSFC 30940096]
- Natural Science Foundation of Chongqing Science & Technology Commission, China [CSTC2010BB5099]
- Ministry of Education, China [20105503110001]
- Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education, China [[2011]508]
- Major Program of Chongqing Medical University [XBZD201006]
- Scientific Research Foundation for the Returned Overseas Scholars of Chongqing Medical University
- National Institutes of Health [R01CA151610]
- Avon Foundation [02-2010-068]
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Aberrant expression of c-Ski oncoprotein in some tumor cells has been shown to be associated with cancer development. However, the role of c-Ski in cancer-associated fibroblasts (CAFs) of tumor microenvironment has not been characterized. In the current study, we found that c-Ski is highly expressed in CAFs derived from breast carcinoma microenvironment and this CAF-associated c-Ski expression is associated with invasion and metastasis of human breast tumors. We showed that c-Ski overexpression in immortalized breast normal fibroblasts (NFs) induces conversion to breast CAFs by repressing p53 and thereby upregulating SDF-1 in NFs. SDF-1 treatment or p53 knockdown in NFs had similar effects on the activation of NFs as c-Ski overexpression. The c-Ski-activated CAFs show increased proliferation, migration, invasion and contraction compared with NFs. Furthermore, c-Ski-activated CAFs facilitated the migration and invasion of MDA-MB-231 breast cancer cells. Our data suggest that c-Ski is an important regulator in the activation of CAFs and may serve as a potential therapeutic target to block breast cancer progression. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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